This invention relates to compositions useful in the preparation of radiodiagnostic agents for use in tissue imaging. More particularly, it relates to compounds used as non-interfering stabilizers for such compositions.
Scintigraphic skeletal imaging and similar radiographic techniques for visualizing other tissues are finding ever-increasing application in biological and medical research and in diagnostic procedures. Generally, scintigraphic procedures involve the preparation of radioactive agents which, upon introduction into a biological subject, become localized in specific organs, tissues, or skeletal structures that are under study. When so localized, traces, plots, or scintiphotos of the distribution of the radiographic materials can be made by various radiation detectors, e.g., transversing scanners and scintilation cameras. The distribution and corresponding relative intensity of the detected radioactive material not only indicates the position occupied by the tissue in which the radionuclide is localized, but also indicates the presence of aberrations, patholidical conditions, and the like.
In general, depending on the type of radionuclide used and the organ of interest, a scintigraphic imaging agent as used in a hospital comprises a radionuclide, a carrier agent designed to target the specific organ, various auxiliary agents which affix the radionuclide to the carrier, water or other delivery vehicles suitable for injection into, or aspiration by, the patient, physiologic buffers and salts, and the like. The carrier attaches or complexes with the radionuclide, and localizes the material in the location where the carrier naturally concentrates in a biologic subject. Certain radionuclides may be used without an additional carrier, such as thallium-201 (.sup.201 Tl) and technetium-99m (.sup.99m Tc), in pertechnetate form, for brain and thyroid imaging.
Technetium-99m is widely known for use in tissue imgaging agents. This radionuclide is conveniently available commercially in the oxidized pertechnetate form (.sup.99m TcO.sub.4.sup.-, hereinafter "pertechnetate-Tc99m"). However, the technetium in pertechnetate has a valence state of +7 and, thus, will not complex with the most commonly used carriers for radionuclide tissue imaging. This problem is easily overcome by reducing the technetium to what is believed to be the +3, +4, and/or +5 oxidation state. Thus, technetium-labeled imaging agents are generally prepared by admixing pertechnetate-Tc99m isotonic saline solution with a technetium reductant (reducing agent) such as the stannous, ferrous, or chromous salt of sulfuric or hydrochloric acid, and the desired carrier agent for targeting the organ of interest. For example, organophosphonates are known as suitable carrier agents which target technetium radionuclide to bone tissue. U.S. Pat. No. 3,983,227, Tofe and Francis, discloses the use of reducing salts with radioactive pertechnetate-Tc99m solutions and organophosphonate bone-seeking carriers to prepare skeletal imaging agents.
Technetium-containing scintigraphic imaging agents are known to be unstable in the presence of oxygen, primarily since oxidation of the reductant and/or the technetium destroys the reduced technetium/targeting carrier complex. Accordingly, such imaging agents are generally made oxygen-free by saturating the compositions with oxygen-free nitrogen gas or by preparing the agents in an oxygen-free atmosphere. Stabilization of imaging agents can also be achieved through chemical means. U.S. Pat. No. 4,232,000, Fawzi, issued Nov. 4, 1980, discloses the use of gentisyl alcohol as a stabilizer for technetium imaging agents. Similarly, U.S. Pat. No. 4,233,284, Fawzi, issued Nov. 11, 1980, discloses the use of gentisic acid as a stabilizer. German Offenlegungsschrift No. 2,618,337, Tofe, published Nov. 11, 1976, discloses the use of ascorbic acid and erythorbic acid as stabilizers with technetium imaging agents.
Commercial products for use in skeletal imaging are generally provided in liquid or dry powder mixture "kits" with vials containing phosphate or phosphonate bone seeking carriers. Skeletal imaging agents are formed by adding pertechnetate-Tc99m, in physiological saline, to such kits.
It has now been discovered that redutic acid and certain compounds structurally-similar to reductic acid are safe, effective, non-interfering stabilizers for agents used in tissue imaging. In a specific mode, phosphate or phosphonate-containing imaging kits containing such stabilizers yield stable imaging agents.